Remyelination failure contributes to progressive neurodegeneration and accumulated clinical disability in multiple sclerosis (MS). The identification of critical pro-remyelinating signals would aide in the development of regenerative therapeutics to enhance remyelination in MS and potentially prevent disease progression. Macrophages are known to play a critical role in remyelination, ranging from debris clearance to promoting oligodendrocyte (OL) differentiation and therefore are an excellent target for pro- remyelinating therapy. But exactly how macrophages regulate OL differentiation/remyelination remains poorly understood. We performed bioinformatic analysis of a comprehensive and temporally resolved transcriptional profile of remyelination from the rat CNS, and identified an immunomodulatory enzyme called interleukin-4 induced gene 1 (IL4i1) in remyelinating lesions. The role of IL4i1 in CNS injury/repair has not previously been suggested. To investigate the role of IL4i1 in CNS remyelination, we will use gain- and loss-of-function strategies in mice by delivery of a recombinant IL4i1 into lesions, and by analysis of IL4i1 deficient mice, respectively Aim 1 will determine if IL4i1 positively regulates OL lineage progression and remyelination. Aim 2 will determine if IL4i1 modulates inflammation during remyelination.